PTBP1 variants displaying altered nucleocytoplasmic distribution are responsible for a neurodevelopmental disorder with skeletal dysplasia

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Abstract

Polypyrimidine tract-binding protein 1 (PTBP1) is a heterogeneous nuclear ribonucleoprotein primarily known for its alternative splicing activity. It shuttles between the nucleus and cytoplasm via partially overlapping N-terminal nuclear localization (NLS) and export (NES) signals. Despite its fundamental role in cell growth and differentiation, its involvement in human disease remains poorly understood. We identified 27 individuals from 25 families harboring de novo or inherited pathogenic variants — predominantly start-loss (89%) and, to a lesser extent, missense (11%) — affecting NES/NLS motifs. Affected individuals presented with a syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short stature with short limbs. Intellectual functioning ranged from normal to moderately delayed. Start-loss variants led to translation initiation from an alternative downstream in-frame methionine, resulting in loss of the NES and the first half of the bipartite NLS, and increased cytoplasmic stability. Start-loss and missense variants shared a DNA methylation episignature in peripheral blood and altered nucleocytoplasmic distribution in vitro and in vivo with preferential accumulation in processing bodies, causing aberrant gene expression but normal RNA splicing. Transcriptomic analysis of patient-derived fibroblasts revealed dysregulated pathways involved in osteochondrogenesis and neurodevelopment. Overall, our findings highlight a cytoplasmic role for PTBP1 in RNA stability and disease pathogenesis.

Authors

Aymeric Masson, Julien Paccaud, Martina Orefice, Estelle Colin, Outi Mäkitie, Valérie Cormier-Daire, Raissa Relator, Sourav Ghosh, Jean-Marc Strub, Christine Schaeffer-Reiss, Carlo Marcelis, David A. Koolen, Rolph Pfundt, Elke de Boer, Lisenka E.L.M. Vissers, Thatjana Gardeitchik, Lonneke A.M. Aarts, Tuula Rinne, Paulien A. Terhal, Nienke E. Verbeek, Linda C. Zuurbier, Astrid S. Plomp, Marja W. Wessels, Stella A. de Man, Arjan Bouman, Lynne M. Bird, Reem Saadeh-Haddad, Maria J. Guillen Sacoto, Richard Person, Catherine Gooch, Anna C.E. Hurst, Michelle L. Thompson, Susan M. Hiatt, Rebecca O. Littlejohn, Elizabeth R. Roeder, Mari Mori, Scott E. Hickey, Jesse M. Hunter, Kristy Lee, Khaled Osman, Rana Halloun, Ruxandra Bachmann-Gagescu, Anita Rauch, Dagmar Wieczorek, Konrad Platzer, Johannes Luppe, Laurence Duplomb-Jego, Fatima El It, Yannis Duffourd, Frédéric Tran Mau-Them, Celine Huber, Christopher T. Gordon, Fulya Taylan, Riikka E. Mäkitie, Alice Costantini, Helena Valta, Stephen Robertson, Gemma Poke, Michel Francoise, Andrea Ciolfi, Marco Tartaglia, Nina Ekhilevitch, Rinat Zaid, Michael A. Levy, Jennifer Kerkhof, Haley McConkey, Julian Delanne, Martin Chevarin, Valentin Vautrot, Valentin Bourgeois, Sylvie Nguyen, Nathalie Marle, Patrick Callier, Hana Safraou, Angela Morgan, David J. Amor, Michael S. Hildebrand, David Coman, Marion Aubert Mucca, Julien Thevenon, Fanny Laffargue, Frédéric Bilan, Céline Pebrel-Richard, Grace Yoon, Michelle M. Axford, Luis A. Pérez-Jurado, Marta Sevilla-Porras, Douglas L. Black, Christophe Philippe, Bekim Sadikovic, Christel Thauvin-Robinet, Laurence Olivier-Faivre, Michela Ori, Quentin Thomas, Antonio Vitobello